Biography of Mahlon DeLong
After World War II, Mahlon DeLong’s family headed west, from Iowa to Newport Beach, California. Young Mahlon and his sister grew up assuming all children went to schools with creative teachers and sandy, ocean-side playgrounds. It would not be the last time that DeLong would find himself, often by chance, in a place - a laboratory, a university, even a part of the brain -- where all the stars converged. And, every time, he made the most of it.
The road to neurology
During his first years at Stanford, DeLong’s long fascination with physics and hard sciences gave way to new interests. He switched his major to history, learned German and Russian, spent his junior year in Berlin, then thought about how much time historians spent locked in libraries. Not for him. Only as a senior, in his first biology course (a requirement for graduation), did DeLong have his "a-ha moment." He says, "I saw chromosomes, cells dividing. I saw life. I realized that the brain held the most interesting problems."
As a graduate student at Stanford, DeLong spent time in the physiologist Don Kennedy’s laboratory, newly set up to study the nervous system of the grasshopper. When DeLong decided he wanted to go to medical school, Kennedy strongly encouraged him to "go east, young man, go east," where Harvard's faculty was rich with neuroscientists and neurologists. DeLong's interest in movement disorders first stirred as an intern attending Saturday morning grand rounds with renowned Harvard neurology chair and movement disorders leader Derrick Denny Brown. DeLong had barely begun his medicine residency in 1967 when his lottery number came up low. Very low. He could either wait to be called up as a soldier, almost certainly to be sent to Viet Nam in the medical corps, or he could apply for a position in the Public Health System, ideally one at the National Institutes of Health, the nation's center of biomedical research.
With strong recommendations from his mentors, he was accepted as a research associate in the National Institute of Mental Health laboratory of Edward Evarts, the psychiatrist/scientist who had perfected the techniques of recording single nerve cell activity in nonhuman primates. In Evarts’ studies, animals were trained to perform various movements, while recordings were made by microelectrodes placed in different parts of the brain. The goal was to understand how the activity of individual brain cells correlated with the initiation of movement of different parts of the body and with specific aspects of movement, such as speed, direction, and amplitude.
Thanks to the draft, DeLong had once again stepped into "the perfect place." Earlier arrivals to the lab already had staked out the "good stuff," however: the obvious parts of the brain, like the motor cortex and cerebellum, clearly known to be important in control of movement. As the latecomer, DeLong got one of the few parts left: the basal ganglia, a collection of complex interconnected brain structures deep in the cerebral hemisphere.
Although the basal ganglia’s involvement with Parkinson’s disease and other movement disorders was known, its function and organization were only beginning to be understood. DeLong’s first thought on looking at it was that “this thing has no paved roads.” But no one had ever adequately applied the techniques of recording nerve activity that DeLong now turned onto the basal ganglia – and the results were dramatic.
Over the next five years, DeLong’s work at the NIH showed that there were strong differences in the spontaneous discharge of neurons in the different nuclei of the basal ganglia. Only specific portions were involved with movement and, just as found in the motor cortex and other portions of the motor system, specific cells in the basal ganglia were active with specific movements. The two big surprises were that the body representation was preserved in the network of nuclei, with separate regions for the leg, arm, and face, and that cells in the basal ganglia did not appear to become active in the onset of movement as early as had been expected, when compared with the motor cortex and cerebellum. This raised persisting questions about the presumed role of basal ganglia in the initiation of movement.
In 1973, when DeLong did pull himself away from research to resume his delayed neurology residency, it was not at Harvard but nearby Johns Hopkins. That was good for wife Mary, a chemist who was doing postdoctoral work at NIH, where she and DeLong met and married, and who recently had joined the Hopkins pharmacology faculty. But Hopkins also proved to be good deal for Mahlon.
The newly arrived Hopkins neurology chair, Guy McKhann, was recruiting some of the best faculty in the country. Without planning it that way, DeLong “had stepped into Camelot.” Like some others of the notable bright young men and women who trained at Hopkins in this golden era, he finished his residency and stayed on as faculty.
At Hopkins, DeLong continued to explore the basal ganglia’s function and organization, changing the then current thinking. His research findings – and a reconsideration of the existing anatomical data – indicated that its structures were not a funnel of diverse influences to the motor cortex but rather components of a series of independent parallel circuits, receiving from and sending information to specific cerebral cortex. And, another big surprise, the circuits were not only involved in movement but also in cognition and emotion.
In 1986, his conclusions were published in Annual Reviews of Neuroscience, quickly becoming one of the most highly cited papers in the field. This proposed schema provided a scaffolding for how to view the segregated functions of these structures, a view important for neurologists and basic neuroscientists – and for psychiatrists. The field of psychiatry was beginning to transition from a purely Freudian approach to a molecular biological one, and the new data provided an anatomical and physiological basis for understanding the diverse role of the basal ganglia in behavior and how cognitive and psychiatric disorders, as well as neurological disorders, could be caused by disturbances in the different circuits or networks of the brain, not just in the mind.
DeLong later told interviewers that he never expected his early interests in understanding what the basal ganglia contributed to the control of movement to have a very practical or clinical outcome.
Thinking of the basal ganglia in terms of PD
In the early 1980s, some drug users’ bad luck was exactly the opposite for the field of neuroscience and for DeLong’s lab in particular. A powder produced in backroom labs and sold on the street as a new synthetic heroin sometimes became contaminated by a close chemical cousin. The Centers for Disease Control and Prevention reported that MPTP-contamination was causing sporadic outbreaks of what the press called “frozen addicts” – mostly young people who suddenly displayed the major clinical signs of Parkinson’s disease, including slowness of movement, muscular rigidity, and tremor. Autopsies showed that MPTP destroyed the brain cells that produced dopamine, the neurotransmitter long associated with Parkinson’s disease. The damage was irreversible but victims responded to L-dopa and other medicines discovered in the 1960s to be effective in the treatment of Parkinson’s.
The finding – and the animal models of Parkinson’s it made possible – was noted by labs across the country, including DeLong’s. The devastating effect of the destruction of dopamine-producing brain cells had been thought, at one time, to indicate that Parkinson’s symptoms resulted from underactivity in cells of the basal ganglia, caused by the lack of this essential neurotransmitter. DeLong’s stunning discovery was that the symptoms of Parkinson’s following the loss of dopamine was not due to a decrease in activity. Instead, it was due to excessive and abnormal activity in the output cells of the basal ganglia, as suggested by circuit models of the disorder.
The prime target was a specific circuit, the motor circuit within a small nucleus of the basal ganglia called the Subthalamic nucleus. The Subthalamic nucleus had been implicated in prior physiological and metabolic imaging studies, and the work of DeLong and colleagues now showed it to be likely at the heart of the problem, by excessively and abnormally driving the basal ganglia output.
The next step was to test the hypothesis that the overactive Subthalamic nucleus was the problem: using an animal model of Parkinson’s, the researchers inactivated the area with a lesion, thus interrupting its output. The results were astonishing. When a lesion was made on one side of the basal ganglia, the tremor and muscular rigidity almost instantaneously melted away on the opposite side of the body. Publication in the journal Science, in 1990, created another whirlwind of excitement.
Emory becomes a national center for movement disorders clinical care and research
About a year before publication of DeLong’s groundbreaking paper on relief from PD symptoms due to basal ganglia lesioning, Emory University sought out DeLong as a possible new chair of neurology, a department and program, which the university was intent on expanding. DeLong quickly realized that Emory had almost everything he could want: resources, supportive leadership, a growing clinical Parkinson’s program, and a national primate research center.
Emory wooed. DeLong wavered. The dean thought DeLong was a great negotiator. His friends knew he was more likely postponing a decision. One thing that turned the tide, says DeLong, was Emory’s willingness to invest in brain imaging, including construction of a new PET center, a proposal that already had considerable support from faculty in Emory’s radiology department. Delong said yes. He brought with him a team of fellows and research and clinical faculty who were working on the basal ganglia, thus greatly expanding Emory’s small neurology department.
In fairly short order, the new William Patterson Timmie Chair of Neurology built or strengthened clinical programs in stroke, epilepsy, neuromuscular disease, Alzheimer’s, and – especially – in movement disorders, where both research and clinical applications of that research kicked into high gear. At Hopkins, he and his colleagues had been doing functional surgical intervention for patients with tremor. At Emory, with colleague Jerrold Vitek and neurosurgeon Roy Bakay, DeLong’s team began exploring pallidotomy, using radiofrequency lesioning to destroy cells in the internal segment of the pallidum, the output nucleus of the basal ganglia, a procedure called “pallidotomy.” Pallidotomy had been used for Parkinson’s, with mixed results, in the 1950s and 1960s, then largely abandoned in the 1970s after the introduction of levodopa.
Many were reluctant to lesion the Subthalamic nucleus, since it was known to cause involuntary movements and out of concern that lesioning this highly vascular structure could cause bleeding. But a lot had changed, much of it in DeLong’s laboratories, since the 1970s. DeLong believed the better understanding of the organization of the circuits of the basal ganglia, together with the improved imaging and electrophysiological mapping techniques, would enable the team to hit the surgical targets more precisely, with better results and fewer side effects. The first pallidotomy at Emory in late 1992 was remarkably successful. Neurologists and neurosurgeons from around the world flocked to see the techniques utilized at Emory. Results from clinical trials at Emory and other institutions showed pallidotomy’s longer-range success. A federally-funded controlled trial of pallidotomy conducted at Emory demonstrated its clear benefit.
The work helped to open the door to other new surgical procedures for treating Parkinson’s disease, in particular, deep brain stimulation (DBS), a less invasive approach developed by French neurosurgeon Alim Benabid. DBS was initially used for tremor with targeting of the thalamus. It was then tried for Parkinson’s using the Subthalamic nucleus (STN) target identified by DeLong’s earlier work in animal models. Whereas lesioning destroys brain cells, high frequency DBS activates them. Small electrodes are placed in the targeted areas and connected to a control device, similar to a cardiac pacemaker, under the skin. The pacemaker can be externally adjusted to deliver continuous stimulation with control of the rate, amplitude and duration of the pulses. Although the precise mechanism of action of DBS is still controversial, high-frequency stimulation acts clinically very much like a lesion and appears to block or override the abnormal activity in the network. Although DBS has not been shown to work better than pallidotomy to alleviate the symptoms of PD, it is reversible and adjustable. Electrical activity can be tuned to achieve optimal benefit and minimize side effects. DBS was eventually approved by the Food and Drug administration as a treatment for Parkinson’s.
And DBS wasn’t just for PD. DeLong had worked with dystonia patients for much of his clinical and research life and was long-time scientific director of the Dystonia Medical Research Foundation. DBS proved to be perhaps more effective for dystonia than for any other neurological disorder, in large part because the disease is not progressive. DeLong and colleagues branched out to dystonia and even to Tourette’s.
The group of researchers and clinicians working with DBS at Emory was greatly strengthened and broadened by the arrival of Dr. Helen Mayberg, a neurologist working with intractable depression. Mayberg was a fellow in nuclear medicine when DeLong was at Hopkins and the two have followed each other’s work for years. Mayberg has studied the circuitry of depression and has devised approaches to treat patients with depression unresponsive to conventional drug and other measures.
In 2003 DeLong stepped down as chair of neurology to take the position of interim director of the Neuroscience Initiative, a university-wide effort to integrate the widespread and highly successful neuroscience programs ac ross schools and departments and to create a multidisciplinary Comprehensive Neuroscience Center, focused on specific disorders such as Alzheimer’s, Parkinson’s, epilepsy, and stroke. In 2006, he relinquished the position of director of neuroscience after recruiting noted neurologist and neuroscientist Dennis Choi to that position.
Over the past two years, he, together with colleagues Robert Gross in neurosurgery and Helen Mayberg in psychiatry, have formed a new multidisciplinary center called eNTICE (Emory Neuromodulation & Technology Innovation Center), which is now partially funded through Emory’s Robert W. Woodruff Health Sciences Center. The goal of eNTICE is “the advancement of neuromodulation and the development of innovative neuromodulation technologies for the treatment of neurological and psychiatric disorders, harnessing the synergy that occurs when basic scientists, clinical researchers, and industry interact in an open, collegial, and creative organizational environment.” Efforts are now underway with Georgia Tech to form a collaboration with eNTICE.
DeLong still works what would be at minimum full-time for an ordinary person. Wife Mary no longer commutes to work at NIH. She now serves as Assistant Dean and Director of the Office of Postgraduate Education in the School of Medicine. Daughter Lori, an Emory medical school graduate, is on the dermatology faculty. Son John also lived in Atlanta after the family’s move here but now lives in the DC area for his job at the National Security Agency. DeLong’s two older children moved to Atlanta as adults. Bryan is a Vice President at Federal Home Loan Bank and Ariane DeLong Chalmers, a Goizueta school of business graduate, works in operations at Emory’s Wesley Woods. Most of the six grandchildren live close by. In his free time, Delong gardens, plays various instruments including the guitar and recorder and, periodically, the alto saxophone that dates back to his swing band days in middle and high school. He gave up running after a recent hip replacement, but he regularly engages in exercise, “the secret to good health.”
He is as committed as ever to work. He remains deeply involved with the deep brain stimulation work, participating in surgery every week and seeing patients referred for surgery and for post-operative programming and care. He is recognized by Castle-Connolly as a "top doctor" for the treatment of movement disorders. Honors have continued to pile up, including the recent 2014 Breakthrough Prize in Life Sciences, which recognizes excellence in research aimed at curing intractable diseases and extending life (see short bio to the side). He is frequently asked to give distinguished lectures all over the country -- and grateful patients have been generous in supporting his ambitions to create an ever stronger, more successful movement disorders program, especially involving neuromodulation.